Alpha, omega-difunctional aldaramides

ABSTRACT

Alpha, omega-difunctional aldaramides, in particular diaminoaldaramides, dihydroxyaldaramides, bis(alkoxycarbonylalkyl)aldaramides, and bis(carboxyalkyl)aldaramides, and processes for preparing the aldaramides are provided.

This application claims benefit of 60/655,647, filed 2/23/2005.

FIELD OF INVENTION

The invention is directed to alpha, omega-difunctional aldaramides andprocesses for preparing them.

BACKGROUND

The concept of using biomass-derived materials to produce other usefulproducts has been explored since man first used plant materials andanimal fur to make clothing and tools. Biomass derived materials havealso been used for centuries as adhesives, solvents, lighting materials,fuels, inks/paints/coatings, colorants, perfumes and medicines.Recently, people have begun to explore the possibility of using “refinedbiomass” as starting materials for chemical conversions leading to novelhigh value-in-use products. Over the past two decades, the cost ofrenewable biomass materials has decreased to a point where many arecompetitive with those derived from petroleum. In addition, manymaterials that cannot be produced simply from petroleum feedstocks arepotentially available from biomass or refined biomass. Many of theseunique, highly functionalized, molecules would be expected to yieldproducts unlike any produced by current chemical processes. “Refinedbiomass” is purified chemical compounds derived from the first or secondround of plant biomass processing. Examples of such materials includecellulose, sucrose, glucose, fructose, sorbitol, erythritol, and variousvegetable oils.

A particularly useful class of refined biomass is that of aldaric acids.Aldaric acids, also known as saccharic acids, are diacids derived fromnaturally occurring sugars. When aldoses are exposed to strong oxidizingagents, such as nitric acid, both the aldehydic carbon atom and thecarbon bearing the primary hydroxyl group are oxidized to carboxylgroups. An attractive feature of these aldaric acids includes the use ofvery inexpensive sugar based feedstocks, which provide low raw materialcosts and ultimately could provide low polymer costs if the properoxidation processes are found. Also, the high functional density ofthese aldaric acids provide unique, high value opportunities, which arecompletely unattainable at a reasonable cost from petroleum-basedfeedstocks.

Aldaric acid derivatives, because of their high functionality, arepotentially valuable monomers and crosslinking agents.

Diaminoaldaramides, dihydroxyaldaramides,bis(alkoxycarbonylalkyl)aldaramides, and bis(carboxyalkyl)aldaramidesare examples of monomers and crosslinking agents that could be prepared.No simple method exists for the preparation of all of these. Hoagland(Carbohydrate Res., 98 (1981) 203-208) studied the kinetics of theaminolysis of diethyl galactarate. This procedure, would not be expectedto produce the same results using the equivalent lactone or dilactone.Reaction of a polyhydroxy diester or dilactone with a diamine has thepotential to produce oligomers and polymer and to undergo various sidereactions. Gorman and Folk (J. Biol. Chem. 1980, 255, 1175-1180) employa 4-step sequence to protect one end of ethylenediamine, react withdiethyl tartrate, and deprotect. It would be expected that an aminoesterwould not react with another ester without competing reaction withitself to form oligopeptides. Pecanha, et al. (WO02/42412) employ afour-step sequence to protect the hydroxyl groups of tartaric acid,activate the carboxyl groups as acyl chloride groups, react with anamino acid ester, and deprotect.

Applicants have discovered new difunctional aldaramides that can be usedas monomers or polymer crosslinkers, and processes for preparing thealdaramides.

SUMMARY OF THE INVENTION

One aspect of the invention is a compound of Formula I

and salts thereof, wherein n=1-6 and R¹ and R² are independentlyoptionally substituted hydrocarbylene groups, wherein the hydrocarbylenegroups are aliphatic or aromatic, linear, branched, or cyclic, andwherein the hydrocarbylene groups optionally contain —O— linkages.

Another aspect of the invention is a compound of Formula V,

and salts thereof, wherein n=1-6; R⁴ and R⁵ are independently optionallysubstituted hydrocarbylene groups, wherein the hydrocarbylene groups arealiphatic or aromatic, linear, branched, or cyclic, and wherein thehydrocarbylene groups optionally contain —O— linkages; and R³ and R⁶ areindependently hydrogen, optionally substituted aryl or optionallysubstituted alkyl.

Another aspect of the invention is a process for preparing a compound ofFormula VII

or a salt thereof, comprising contacting at least one diamine of theformula NH₂—R⁷—NH₂ with a compound of Formula VIII, IX, or X

wherein R⁷ is an optionally substituted hydrocarbylene group, whereinthe hydrocarbylene group is aliphatic or aromatic, linear, branched, orcyclic, and wherein the hydrocarbylene group optionally contains —O—linkages, R′ and R″ are independently a 1 to 6 carbon alkyl group,n=1-6, m=0-4, and p=1-4.

Another aspect of the invention is a process for preparing a compound ofFormula XIX

or a salt thereof, comprising contacting at least one amino acid oramino acid ester of the formula (R⁸OOC)—R⁹—NH₂ with a compound ofFormula VIII, IX, or X, wherein n=1-6; R⁹ is an optionally substitutedhydrocarbylene group, wherein the hydrocarbylene group is aliphatic oraromatic, linear, branched, or cyclic, and wherein the hydrocarbylenegroup optionally contains —O— linkages, R⁸ is hydrogen or alkyl, R′ andR″ are independently a 1 to 6 carbon alkyl group, n=1-6, m=0-4, andp=1-4.

Another aspect of the invention is a process for preparing a compound ofthe Formula XXII

or salts thereof, comprising contacting at least one aminoalcohol of theFormula HO—R¹⁰—NH₂ with a compound of Formula VIII or X wherein R¹⁰ isan optionally substituted hydrocarbylene group, wherein thehydrocarbylene group is aliphatic or aromatic, linear, branched, orcyclic, and wherein the hydrocarbylene group optionally contains —O—linkages, R′ is a 1 to 6 carbon alkyl group, m=0-4, and p=1-4.

DETAILED DESCRIPTION

The following definitions can be used for the interpretation of thespecification and the claims:

By hydrocarbyl is meant a straight chain, branched or cyclic arrangementof carbon atoms connected by single, double, or triple carbon-to-carbonbonds, and substituted accordingly with hydrogen atoms. Hydrocarbylgroups can be aliphatic and/or aromatic. Examples of hydrocarbyl groupsinclude methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl,cyclopropyl, cyclobutyl, cyclopentyl, methylcyclopentyl, cyclohexyl,methylcyclohexyl, benzyl, phenyl, o-tolyl, m-tolyl, p-tolyl, xylyl,vinyl, allyl, butenyl, cyclohexenyl, cyclooctenyl, cyclooctadienyl, andbutynyl. Examples of substituted hydrocarbyl groups include tolyl,chlorobenzyl, —(CH₂)—O—(CH₂)—, fluoroethyl, p-(CH₃S)C₆H₅,2-methoxypropyl, and (CH₃)₃SiCH₂.

“Alkyl” means a saturated hydrocarbyl group. Examples of alkyl groupsinclude methyl, ethyl, propyl, isopropyl, butyl, s-butyl, isobutyl,pentyl, neopentyl, hexyl, heptyl, isoheptyl, 2-ethylhexyl, cyclohexyland octyl.

“Aryl” means a group defined as a monovalent radical formed conceptuallyby removal of a hydrogen atom from a hydrocarbon that is structurallycomposed entirely of one or more benzene rings. Examples of aryl groupsinclude benzene, biphenyl, terphenyl, naphthalene, phenyl naphthalene,and naphthylbenzene.

‘Alkylene’ and ‘arylene’ refer to the divalent forms of thecorresponding alkyl and aryl groups. ‘Hydrocarbylene’ groups include‘alkylene’ groups, ‘arylene’ groups, and groups that can be representedby connecting some combination of alkylene and arylene groups.“Divalent”, as used herein, means that the group can form two bonds.

“Substituted” and “substituent” mean a group is substituted and containsone or more substituent groups, or “substituents,” that do not cause thecompound to be unstable or unsuitable for the use or reaction intended.Unless otherwise specified herein, when a group is stated to be“substituted” or “optionally substituted”, substituent groups that canbe present include amide, nitrile, ether, ester, halo, amino (includingprimary, secondary and tertiary amino), hydroxy, oxo, vinylidene orsubstituted vinylidene, silyl or substituted silyl, nitro, nitroso, andthioether.

The present invention is directed to difunctional aldaramides, includingthose that are useful as monomers or crosslinking agents for polymers.Co-pending patent application Ser. Nos. 11/064,191 and 11/064,192describe the use of some such materials in the preparation ofcross-linked polymers.

Aldaric acids are diacids derived from naturally occurring sugars. Whenaldoses are exposed to strong oxidizing agents, such as nitric acid,both the aldehydic carbon atom and the carbon bearing the primaryhydroxyl group are oxidized to carboxyl groups. This family of diacidsis known as aldaric acids (or saccharic acids). An aldarolactone has onecarboxylic acid lactonized; the aldarodilactone has both lactonized. Asillustration, the aldaric acid derivatives starting from D-glucose areshown below.

The compounds of the present invention and their starting materials canbe made from aldaric acids or their derivatives, or from any othersource. Any stereoisomer or mixture of stereoisomers can be used in thecompositions and processes disclosed herein.

In some embodiments, the present invention provides compounds of FormulaI and salts thereof, wherein n=1-6 and R¹ and R² are independentlyoptionally substituted hydrocarbylene groups, wherein the hydrocarbylenegroups are aliphatic or aromatic, linear, branched, or cyclic, andwherein the hydrocarbylene groups optionally contain —O— linkages. Insome preferred embodiments, n=4.

R¹ and R² can be the same or different, and can independently bealkylene, polyoxaalkylene, or arylene groups, linear or branched,wherein the alkylene, polyoxaalkylene, or arylene groups are optionallysubstituted with NH₂ or alkyl. When R¹ or R² is alkylene, it can havefrom 2 to 20 carbon atoms, preferably from 2 to 8.

By “polyoxaalkylene” is meant linear or branched alkyl groups linked byether linkages. Polyoxaalkylene can contain 2 carbons up to polymericlength units. Examples of polymeric polyoxaalkylenes suitable for thepresent inventions include poly(ethylene glycols), poly(propyleneglycols), polyoxetane, and poly(tetramethylene glycols) such as thosebased on Terathane® polytetramethylene ether glycol (E. I. DuPont deNemours, Wilmington, Del.).

R¹ and R² can also be independently —CH₂—CH₂—, ——CH₂(CH₂)₄CH₂—, FormulaII, Formula III, or Formula IV,

wherein the open valences indicate where R¹ and R² attach to thenitrogens in Formula I. In Formula IV, either open valence can beattached to the terminal, primary amino (NH₂) group.

In other embodiments, the present invention provides compounds ofFormula V,

and salts thereof, wherein n=1-6; R⁴ and R⁵ are independently optionallysubstituted hydrocarbylene groups, wherein the hydrocarbylene groups arealiphatic or aromatic, linear, branched, or cyclic, and wherein thehydrocarbylene groups optionally contain —O— linkages; and R³ and R⁶ areindependently hydrogen, optionally substituted aryl or optionallysubstituted alkyl.

R⁴ and R⁵ can be the same or different, and can independently bealkylene, polyoxaalkylene, or arylene groups, linear or branched,wherein the alkylene, polyoxaalkylene, or arylene groups are optionallysubstituted with NH₂ or alkyl. R⁴ and R⁵ can also be —CH₂—, —CH₂(CH₃)—,—CH₂(CH₂)₂CH₂—, —CH(NH₂)(CH₂)₄—, or—CH[NHC(═O)O-tert-butyl]CH₂CH₂CH₂CH₂—. The open valences in the aboveformulae indicate where R⁴ and R⁵ are attached to the nitrogen andcarbonyl carbon in Formula V. Where R⁴ and R⁵ are unsymmetrical, bothorientations are intended, unless the resulting chemical structure isunstable.

In some embodiments, R⁴ and/or R⁵ can be an alkylene, polyoxaalkylene,heteroarylene, or arylene group, linear or branched, wherein thealkylene, polyoxaalkylene, heteroarylene or arylene group is optionallysubstituted with NH₂, aryl including heteroaryl, or alkyl. In someembodiments, n is 4. When R⁴ and/or R⁵ is alkylene, it can have from 1to 12 carbon atoms, preferably from 1 to 6. Also, “arylene” is intendedto include arenedialkylene, e.g.,.

When R⁴ and/or R⁵ is arylene, it can have from 2 to 12 carbon atoms,preferably 4 to 6. For example, when R⁴ and/or R⁵ has two carbon atoms,it can be a heteroarylene, e.g., a triazole ring. When R⁴ and/or R⁵ has12 carbon atoms, it can be, for example, a biphenyl. When R⁴ and/or R⁵has 4 carbon atoms, examples are furan or pyrrole rings.

When R⁴ and/or R⁵ is polyoxaalkylene, it can have from 1 to 50 repeatunits, preferably from 1 to 10. The total number of carbons depends onthe number of carbons in the repeat unit.

In some embodiments, n=4. R³ and R⁶ can be the same or different, andcan independently be hydrogen or methyl.

Also provided are processes for preparing difunctional aldaramides.

In some embodiments, the invention provides processes for preparingcompounds of Formula VII

and salts thereof, comprising contacting at least one diamine of theformula NH₂—R⁷—NH₂ with a compound of Formula VIII, IX, or X, shownbelow,

wherein R⁷ is an optionally substituted hydrocarbylene group, whereinthe hydrocarbylene group is aliphatic or aromatic, linear, branched, orcyclic, and wherein the hydrocarbylene group optionally contains —O—linkages, R′ and R″ are independently a 1 to 6 carbon alkyl group,n=1-6, m=0-4, and p=1-4. In some embodiments of the invention, n=4.

R⁷ can be an alkylene, polyoxaalkylene, or arylene group, linear orbranched, wherein the alkylene, polyoxaalkylene, or arylene group isoptionally substituted with NH₂ or alkyl. The diamine can also beH₂NCH₂CH₂NH₂, H₂NCH₂(CH₂)₄CH₂NH₂, Formula XI, Formula XII, or FormulaXIII, shown below. With Formula XIII, either amino group can react toform the amide bonds in Formula VII and, thus, either of the two aminogroups of Formula XIII can remain as the residual primary amino (NH₂)groups in Formula VII.

When R⁷ is alkylene, it can have from 1 to 12 carbon atoms, preferablyfrom 1 to 6. Also, “arylene” is intended to include arenedialkylene,e.g.,

When R⁷ is arylene, it can have from 2 to 12 carbon atoms, preferably 4to 6. For example, when R⁷ has two carbon atoms, it can be aheteroarylene, e.g., a triazole ring. When R⁷ has 12 carbon atoms, itcan be, for example, a biphenyl. When R⁷ has 4 carbon atoms, examplesare furan or pyrrole rings. When R⁷ is polyoxaalkylene, it can have from1 to 50 repeat units, preferably from 1 to 10. The total number ofcarbons depends on the number of carbons in the repeat unit.

In some embodiments, there are provided processes for preparingcompounds of Formula XIX

and salts thereof, comprising contacting at least one amino acid oramino acid ester of the formula (R⁸OOC)—R⁹—NH₂ with a compound ofFormula VIII, IX, or X, wherein n=1-6; R⁹ is an optionally substitutedhydrocarbylene group, wherein the hydrocarbylene group is aliphatic oraromatic, linear, branched, or cyclic, and wherein the hydrocarbylenegroup optionally contains —O— linkages, R⁸ is hydrogen or alkyl, R′ andR″ are independently a 1 to 6 carbon alkyl group, n=1-6, m=0-4, andp=1-4.

In some embodiments, R⁹ can be an alkylene, polyoxaalkylene,heteroarylene, or arylene group, linear or branched, wherein thealkylene, polyoxaalkylene, heteroarylene or arylene group is optionallysubstituted with NH₂, aryl including heteroaryl, or alkyl. In someembodiments, n is 4. When R⁹ is alkylene, it can have from 1 to 12carbon atoms, preferably from 1 to 6. Also, “arylene” is intended toinclude arenedialkylene, e.g.,

When R⁹ is arylene, it can have from 2 to 12 carbon atoms, preferably 4to 6. For example, when R⁹ has two carbon atoms, it can be aheteroarylene, e.g., a triazole ring. When R⁹ has 12 carbon atoms, itcan be, for example, a biphenyl. When R⁹ has 4 carbon atoms, examplesare furan or pyrrole rings. When R⁹ is polyoxaalkylene, it can have from1 to 50 repeat units, preferably from 1 to 10. The total number ofcarbons depends on the number of carbons in the repeat unit.

The amino acid or amino acid ester can be H₂NCH₂C(═O)OCH₃,H₂NCH(CH₃)C(═O)OCH₃, H₂N(CH₂)₄CH(NH₂)C(═O)OCH₃, H₂NCH(CH₃)C(═O)OH,H₂N(CH₂)₄CH(NH₂)C(═O)OH, or Formula XX, shown below.

Also provided is a process for preparing compounds of the Formula XXII

and salts thereof, comprising contacting at least one aminoalcohol offormula HO—R¹⁰—NH₂ with a compound of Formula VIII or X wherein R¹⁰ isan optionally substituted hydrocarbylene group, wherein thehydrocarbylene group is aliphatic or aromatic, linear, branched, orcyclic, and wherein the hydrocarbylene group optionally contains —O—linkages.

R¹⁰ can be an alkylene, polyoxaalkylene, or arylene group, linear orbranched, wherein the alkylene, polyoxaalkylene, or arylene group isoptionally substituted with NH₂ or alkyl. The aminoalcohol can beHO—(CH₂)₂—NH₂, HO—(CH₂)₃—NH₂, or 4-(2-aminoethyl)-phenol.

When R¹⁰ is alkylene, it can have from 1 to 12 carbon atoms, preferablyfrom 1 to 6. Also, “arylene” is intended to include arenedialkylene,e.g.,

When R¹⁰ is arylene, it can have from 2 to 12 carbon atoms, preferably 4to 6. For example, when R¹⁰ has two carbon atoms, it can be aheteroarylene, e.g., a triazole ring. When R¹⁰ has 12 carbon atoms, itcan be, for example, a biphenyl. When R¹⁰ has 4 carbon atoms, examplesare furan or pyrrole rings. When R¹⁰ is polyoxaalkylene, it can havefrom 1 to 50 repeat units, preferably from 1 to 10. The total number ofcarbons depends on the number of carbons in the repeat unit.

The processes of the instant invention can be run at any suitabletemperature but preferably at about 20° C. to about 130° C. Theprocesses can also be prepared in the liquid phase or in the absence ofany solvent. If prepared in the liquid phase, the reactants can bedissolved in a suitable solvent or mixture of solvents. The choice ofsolvent is not critical provided the solvent dissolves or disperses thereactants sufficiently to enable them to react within three days at atemperature of about 20° C. to about 130° C. and is not detrimental toreactant or product. Preferred solvents include water,dimethylformamide, dimethylformamide LiCl, dimethylacetamide,dimethylacetamide LiCl, ethanol, and methanol.

EXAMPLES

The present invention is further defined in the following Examples. Itshould be understood that these Examples, while indicating preferredembodiments of the invention, are given by way of illustration only.From the above discussion and these Examples, one skilled in the art canascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various uses andconditions.

Diaminoaldaramides Example 1 N¹,N⁶-Bis(6-aminohexyl)galactaramide

To a 250-mL 3-neck round-bottom flask equipped with a heating mantle,reflux condenser, nitrogen inlet, and overhead stirrer were added 100 mLof a solution of LiCl (3.8 wt %) in dimethylacetamide (DMAC) and 10.0 g(0.042 mol) of dimethyl galactarate (DMG). The mixture was heated to 55°C. for about 80 minutes, after which a cloudy yellow mixture wasobtained. To this stirred mixture was added 48.0 g (0.414 mol) ofhexamethylenediamine (HMD). Within 5 minutes, the reaction temperatureincreased to 60° C., and a clear yellow solution was obtained. After anadditional 5 minutes of stirring, a pale yellow precipitate formed. Thereaction mixture was heated at 55° C. for an additional 5 hours. It wasthen left to cool overnight, after which the precipitate was collectedby filtration, washed three times with THF, and dried in a vacuum ovenat 60° C. to yield 26.4 g of crude product as white crystals. NMRrevealed a large excess of HMD present. The crude product wasrecrystallized from ethanol and dried in a vacuum oven at 80° C. toyield 16.3 g (96%) purified product. T_(m) (DSC): 178° C.; T_(dec)(TGA): 160° C. (onset).

Example 2 N¹,N⁶-Bis(2-aminoethyl)galactaramide

To a 250-mL 3-neck round-bottom flask equipped with a heating mantle,reflux condenser, nitrogen inlet, and overhead stirrer were added 100 mLof a solution of LiCl (3.8 wt %) in DMAC and 10.0 g (0.042 mol) ofdimethyl galactarate (DMG). The mixture was heated to 55° C. for about80 minutes. Ethylenediamine (26.0 g, 0.433 mol) was added. The mixturewas heated at 55° C. for 5 hours and then cooled to room temperature.The resulting precipitate was collected by filtration, washed threetimes with THF, and dried in a vacuum oven at 60° C. to yield 18.60 g ofcrude product as white crystals. Recrystallization from ethanol anddrying in a vacuum oven at 80° C. gave 10.93 g (89%) of purifiedproduct. T_(m) (DSC): 217° C.; T_(dec) (TGA): 190° C. (onset).

Example 3 N¹,N⁶-Bis(6-aminohexyl)-D-glucaramide

To an oven-dried 20-mL scintillation vial equipped with a magnetic stirbar, in a dry box, were added D-glucaro-1,4:6,3-dilactone (GDL, 0.87 g,4.98 mmol) dissolved in 3 mL of methanol followed by a solution of HMD(2.32 g, 19.9 mmol) in 5 mL of methanol. The mixture was stirred atambient temperature for 18 hours. Additional methanol (10 mL) was addedand the thick slurry was stirred at ambient temperature for anadditional 5 days. The mixture was filtered and washed with methanol (30mL) before vacuum drying to give an off-white solid (0.92 g, 45% yield).¹H NMR (300 MHz, DMSO-d₆) δ 7.81 (br, 1H), 7.57 (t, J=5.5 Hz, 1H), 3.97(d, J=3.7 Hz, 1H), 3.92 (d, J=6.3 Hz, 1H), 3.86 (t, J=3.4 Hz, 1H), 3.68(dd, J=3.0, 6.3 Hz, 1H), 3.41 (br, 8H), 3.07 (m, 4H), 2.51 (t, J=6.5 Hz,4H), 1.41 (m, 4H), 1.26 (m, 12H). ¹³C NMR (75 MHz, DMSO-d₆) δ 173.23,172.27, 73.40, 73.14, 71.79, 70.57, 41.64 (2C), 38.45, 38.36, 33.24(2C), 29.32, 29.22, 26.42 (2C), 26.27 (2C).

Example 4 N¹,N⁶-Bis(2-aminoethyl)-D-glucaramide

To a 250-mL 3-neck round-bottom flask equipped with a heating mantle,reflux condenser, nitrogen inlet, and overhead stirrer were added 50 mLof DMAC and 17.2 g (0.287 mol) of ethylenediamine. To the homogeneoussolution formed was added, at room temperature, a solution of 5.0 g(0.0287 mol) of GDL dissolved in 25 mL of DMAC. At this point, heat wasapplied to the resulting homogeneous reaction mixture. When thetemperature of the solution reached 38° C. after about 15 minutes ofheating, a precipitate began to develop. The reaction temperature wasincreased to 50° C., and was held there for an additional 24 hours. Thereaction mixture was cooled and then poured into about 100 mL of THF.The resulting precipitate was filtered, washed with THF, and dried in avacuum oven at 80° C. to yield 6.92 g (82%) of a creamy white solid.T_(m) (DSC): 181° C.; T_(dec) (TGA): 170° C. (onset).

Example 5 N¹,N⁶-Bis(2-aminoethyl)-D-glucaramide (Alternate Preparation)

To 48.9 g (814 mmol) of ethylenediamine dissolved in 400 mL of methanolwere added dropwise, at room temperature, 22.18 g (127 mmol) of GDLdissolved in 100 mL of methanol. After stirring overnight at roomtemperature, the mixture was filtered. The precipitate was washed withmethanol and dried under vacuum to give 33.1 g (89%) of a white solidthat was an approximately 87:13 mixture of the 2:1 and 3:2 adducts ofethylenediamine and GDL. ¹H NMR of N¹,N⁶-bis(2-aminoethyl)-D-glucaramide(500 MHz, DMSO-d₆) δ 4.33 (d, J=3.1 Hz, 1H), 4.25 (d, J=5.2 Hz, 1H),4.09 (dd, J=3.1, 4.7 Hz, 1H), 3.97 (t, J=5.0 Hz, 1H), 3.31 (m, 4H), 2.75(m, 4H). ¹³C NMR of N¹,N⁶-bis(2-aminoethyl)-D-glucaramide (126 MHz,DMSO-d₆) δ 175.30, 174.93, 73.62, 73.32, 73.04, 71.48, 41.95, 41.88,40.41 (2C).

When the reaction was run similarly except using 10 mole equivalents ofethylenediamine relative to GDL, the ratio of 2:1 adduct to 3:2 adductincreased to about 95:5.

Example 6 N¹,N⁶-Bis(3-aminophenyl)galactaramide

In a dry box, m-phenylenediamine (MPD, 0.92 g, 8.51 mmol) and DMG (0.51g, 2.13 mmol) were weighed into an oven-dried 50-mL Schlenk tube. Ametal spatula was used to grind the crystalline MPD and homogenize thereaction mixture. The mixture was heated under an atmosphere of nitrogento 130° C. for 17 hours. ¹H and ¹³C NMR (DMSO-d₆) indicated >95%conversion to the desired product with the remainder being methylN-(3-aminophenyl)galactaramate. Heating the mixture to 130° C. for anadditional three days increased conversion, but not to completion.Washing the reaction mixture with methylene chloride (85 mL) removedmost of the excess MPD and halved the amount of methylN-(3-aminophenyl)galactaramate. Subsequent recrystallization fromDMAC/ether removed essentially all of the MPD and methylN-(3-aminophenyl)galactaramate. ¹H NMR (500 MHz, DMSO-d₆) δ 9.02 (s,2H), 7.00 (s, 2H), 6.92 (t, J=7.9 Hz, 2H), 6.73 (d, J=8.0 Hz, 2H), 6.27(d, J=8.0 Hz, 2H), 5.56 (d, J=7.1 Hz, 2H), 5.03 (br, 2H), 4.62 (m, 2H),4.27 (d, J=7.0 Hz, 2H), 3.88 (m, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ172.06, 149.17, 139.16,129.08,109.65, 107.34, 105.00, 71.39, 71.21.

Example 7 N¹,N⁶-Bis(3-aminophenyl)-D-glucaramide

In a dry box, MPD (0.67 g, 6.21 mmol) and GDL (0.27 g, 1.55 mmol) wereweighed into an oven-dried, 20-mL scintillation vial. A metal spatulawas used to grind the crystalline MPD and homogenize the reactionmixture. The vial was heated to 100° C. for 17 hours and then cooled toroom temperature. The resulting glassy solid was broken up and extractedwith methylene chloride to remove excess MPD. ¹H NMR (500 MHz, DMSO-d₆)δ 9.36 (s, 1H), 9.11 (s, 1H), 7.041 (s, 1H), 7.037 (s, 1H), 6.95 (t,J=8.0 Hz, 1H), 6.94 (t, J=8.0 Hz, 1H), 6.78 (m, 2H), 6.30 (m, 2H), 4.23(d, J=3.7 Hz, 1H), 4.11 (d, J=7.1 Hz, 1H), 4.05 (t, J=3.5 Hz, 1H), 3.84(dd, J=3.7, 6.5 Hz, 1H). ¹³C NMR (126 MHz, DMSO-d₆) δ 171.33, 170.83,148.93, 148.88, 139.23, 138.94, 128.90, 128.84, 109.62, 109.52, 107.52,107.46, 105.19, 105.11, 73.75, 73.18, 72.53, 70.53.

Example 8 N¹,N⁶-Bis(4-aminobenzyl)galactaramide

In a dry box, a solution of 4-aminobenzylamine (5.05 mL, 44.5 mmol) inDMSO (25 mL) was added to a slurry of DMG (5.05 g, 21.2 mmol) in DMSO(40 mL) in an oven-dried 200-mL round-bottom flask equipped with amagnetic stirbar. The resulting mixture was stirred at ambienttemperature for five days and then filtered. The collected solid waswashed with DMSO (10 mL) followed by methanol (75 mL) and then driedunder vacuum to give a white solid (4.86 g). Water (400 mL) was added tothe filtrate from the original reaction, and the mixture was stirred for1 hour and then filtered. The recovered solid was washed with water (200mL) followed by methanol (150 mL) and then dried under vacuum to give asecond crop of white solid (2.93 g, 88% overall yield, 97+% purity). ¹HNMR (DMSO-d₆) δ 7.72 (t, J=5.8 Hz, 2H), 6.94 (d, J=8.1 Hz, 4H), 6.49 (d,J=8.2 Hz, 4H), 5.19 (d, J=7.0 Hz, 2H), 4.89 (s, 4H), 4.38 (d, J=6 Hz,2H), 4.16 (m, 6H), 3.82 (d, J=5.8 Hz, 2H). ¹³C NMR (DMSO-_(d6)) δ 173.0,147.4, 128.2, 126.3, 113.7, 70.8, 70.7, 41.7.

Example 9 N¹,N⁶-Bis(4-aminobenzyl)-D-glucaramide

In a dry box, 4-aminobenzylamine (7.33 mL, 64.7 mmol) was weighed intoan oven-dried, 100-mL round-bottom flask equipped with a magneticstirbar. Methanol (7 mL) and then a solution of GDL (5.00 g, 28.7 mmol)in methanol (10 mL) were added. Significant precipitation requiredaddition of methanol (60 mL) to maintain stirring. The resulting slurrywas stirred at ambient temperature for 24 hours and then filtered. Theprecipitate was washed with methanol (160 mL) and dried under vacuum togive a white solid (11.03 g, 92% crude yield). ¹H and ¹³C NMR indicatedthat the product contained 4 mole % methylN-(4-aminobenzyl)-D-glucaramate. Conversion was completed by reacting aportion of the crude product (10.38 g , 24.8 mmol) in 25 mL of DMSO with4-aminobenzylamine (282 μL, 2.49 mmol) overnight at ambient temperature.The mixture was diluted with 75 mL of methanol and stirred several morehours. The resulting precipitate was isolated by filtration, washed withmethanol (200 mL), and dried under vacuum to give a white solid (10.51g, 100% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 8.04 (t, J=5.9 Hz, 1H), 7.77(t, J=5.9 Hz, 1H), 6.94 (dd, J=2.5, 8.4 Hz, 4H), 6.50 (d, J=8.3 Hz, 4H),5.53 (d, J=6.1 Hz, 1H), 5.37 (d, J=5.4 Hz, 1H), 4.91 (s, 4H), 4.76 (d,J=4.5 Hz, 1H), 4.62 (d, J=6.8 Hz, 1H), 4.15 (m, 4H), 4.07 (dd, J=2.7,5.6, 1H), 3.99 (t, J=6 Hz, 1H), 3.96 (dt, J=6.5, 3 Hz, 1H), 3.77 (m,1H). ¹³C NMR (126 MHz, DMSO-d₆) δ 173.01, 172.12, 147.60, 147.58,128.44, 128.41, 126.45, 126.29, 113.88 (2C), 73.56, 73.23, 71.88, 70.60,41.85, 41.79.

Example 10N¹,N⁶-Bis[(5-amino-1,3,3-trimethylcyclohexyl)methyl]galactaramide

DMG (1.00 g, 4.20 mmol) was heated at reflux for 2 hours in a solutionof isophoronediamine (2.87 g, 16.9 mmol) in 20 mL of methanol. After themixture had cooled and the solvent had been removed under reducedpressure, the resulting white solid was stirred for 1 hour in 100 mL ofether and filtered. The solid was washed further with three 20-mLportions of ether and then dried under vacuum to give 2.0 g (93% yield).LC-MS indicated that the product was a 7:1 mixture of the 2:1 and 3:2adducts of isophoronediamine and DMG. The 2:1 adduct appeared as M+H⁺,having an m/e of 515. The 3:2 adduct appeared as M+2H⁺, having an m/e of430. ¹H NMR (500 MHz, DMSO-d₆) δ 7.32 (br s, 1H), 7.18 (br s, 1H),4.16-4.09 (m, 2H), 3.78 (m, 2H), 2.86 (m, 4H), 3.95, 3.40 and 2.20 (3 m,1H), 1.48 (m, 5H), 1.13-0.65 (m, 26H). ¹³C NMR (126 MHz, DMSO-d₆) δ173.54, 172.54, 70.93 (4C), 52.38, 52.26, 49.75, 49.45, 47.22, 47.00,44.98, 44.85, 43.77, 43.61, 36.44 (2C), 35.43 (2C), 31.72 (2C), 28.02,27.81, 23.65 (2C).

Alternately, DMG (1.00 g, 4.20 mmol) and isophoronediamine (6.00 g, 35.2mmol) were heated at 100° C. for 5 to 16 hours under a stream ofnitrogen. The resulting glassy solid was triturated and washed withether to give the product as a white granular solid.

Example 11N¹,N⁶-Bis[(5-amino-1,3,3-trimethylcyclohexyl)methyl]-D-glucaramide

GDL (2.00 g, 11.5 mmol) was added slowly to a solution ofisophoronediamine (7.80 g, 45.8 mmol) in 25 mL of methanol. The mixturewas stirred at room temperature for 1 hour and then at reflux foranother hour. After the mixture had cooled and the solvent had beenremoved under reduced pressure, the resulting white solid was stirredfor 1 hour in 100 mL of ether and filtered. The solid was washed furtherwith three 25-mL portions of ether and then dried under vacuum to give5.36 g (91% yield). LC-MS indicated that the product was a 77:20:3mixture of the 2:1, 3:2, and 4:3 adducts of isophoronediamine and GDL.The 2:1 adduct appeared as M+H⁺, having an m/e of 515. The 3:2 and 4:3adducts appeared as M+2H⁺, having an m/e of 430 and 602, respectively.Exact mass calculated for C₂₆H₅₀N₄O₄ (M+H⁺) 515.3809, found 515.3801. ¹HNMR (500 MHz, DMSO-d₆) δ 7.64-7.522 (m, 1H), 7.38-7.18 (m, 1H), 4.03 (brs, 1H), 3.98 (d, J=6.3 Hz, 1H), 3.88 (br s, 1H), 3.69 (m, 1H), 3.95,3.52, 3.43 and 2.20 (4 m, 1H), 2.86 (m, 4H), 1.48 (m, 5H), 1.13-0.65 (m,26H). ¹³C NMR (126 MHz, DMSO-d₆) δ 173.44, 172.46, 73.28 (2C), 71.74,70.63, 52.38 (2C), 49.38 (2C), 47.08 (2C), 44.96 (2C), 43.56 (2C), 36.45(2C), 35.34 (2C), 31.67 (2C), 27.97 (2C), 23.67 (2C).

Example 12N¹,N⁴-Bis[(5-amino-1,3,3-trimethylcyclohexyl)methyl]-L-tartaramide

Isophoronediamine (3.30 g, 19.4 mmol) and diethyl L-tartrate (1.00 g,4.85 mmol) were combined in a 100-mL round-bottom flask and heated at92° C. under a stream of nitrogen for 1 hour. The mixture was cooled,stirred for 1 hour in 100 mL of ether, and filtered. The solid collectedwas washed further with three 20-mL portions of ether and then driedunder vacuum to give 1.88 g (85% yield). LC-MS indicated that theproduct was a 84:16 mixture of the 2:1 and 3:2 adducts ofisophoronediamine and diethyl L-tartrate. The 2:1 adduct appeared asM+H⁺, having an m/e of 455. The 3:2 adduct appeared as. M+2H⁺, having anm/e of 370. Exact mass calculated for C₂₄H₄₇N₄O₄ (M+H⁺) 455.3597, found455.3581. ¹H NMR (500 MHz, DMSO-d₆) δ 7.39 (t, J=6.2 Hz, 1H), 7.33-7.25(m, 1H), 4.26-4.16 (m, 2H), 3.96, 3.44 and 2.20 (3 m, 1H), 2.86 (m, 4H),1.47 (m, 5H), 1.13-0.60 (m, 26H). ¹³C NMR (126 MHz, DMSO-d₆) δ 172.16(2C), 72.84 (2C), 52.47, 52.42, 49.70, 49.64, 47.18, 47.02, 45.21,45.11, 43.54 (2C), 36.41 (2C), 35.35 (2C), 31.69 (2C), 28.00, 27.97,23.64, 23.60.

Dihydroxyaldaramides Example 13 N¹,N⁶-Bis(2-hydroxyethyl)-D-glucaramide

In a dry box, ethanolamine (0.72 mL, 11.8 mmol) was weighed into anoven-dried, 20-mL scintillation vial equipped with a magnetic stirbar.Methanol (1 mL) was added, and the solution was treated with a solutionof GDL (1.00 g, 5.77 mmol) in methanol (3.5 mL). The resulting slurrywas stirred at ambient temperature for 25 hours. The white solid formedwas recovered by filtration, washed with methanol (18 mL), and driedunder vacuum to give 1.02 g. The mother liquor was concentrated, and theresulting white solid was collected by filtration, washed with coldmethanol (2 mL), and dried under vacuum to give an additional 0.21 g(73% overall yield). ¹H NMR (DMSO-d₆) δ 7.75 (t, J5.6 Hz, 1H), 7.54 (t,J=5.7 Hz, 1H), 5.55 (d, J=6.2 Hz, 1H), 5.38 (d, J=5.2 Hz, 1H), 4.73 (d,J=4.9 Hz, 1H), 4.65 (t, J=5.3 Hz, 2H), 4.57 (d, J=6.7 Hz, 1H), 3.99 (t,J=4.4 Hz, 1H), 3.94 (t, J=6.1 Hz, 1H), 3.87 (m, 1H), 3.71 (m, 1H), 3.41(m, 4H), 3.16 (m, 4H). ¹³C NMR (DMSO-d₆) δ 173.2, 172.4, 73.2, 72.8,71.7, 70.3, 59.8, 59.7, 41.1, 41.0.

Example 14 N¹,N⁶-Bis(3-hydroxypropyl)-D-glucaramide

In a dry box, 3-amino-1-propanol (1.05 mL, 13.8 mmol) was weighed intoan oven-dried, 20-mL scintillation vial equipped with a magneticstirbar. Methanol (1 mL) was added, and the solution was treated with asolution of GDL (1.17 g, 6.71 mmol) in methanol (5 mL). The resultingslurry was stirred at ambient temperature for 24 hours. The white solidformed was recovered by filtration, washed with methanol (18 mL), anddried under vacuum to give 1.74 g (80% yield). ¹H NMR (DMSO-d₆) δ 7.82(t, J=5.7 Hz, 1H), 7.62 (t, J=5.8 Hz, 1H), 5.49 (d, J=6.0 Hz, 1H), 5.33(d, J=4.9 Hz, 1H), 4.70 (d, J=4.6 Hz, 1H), 4.56 (d, J=6.6 Hz, 1H), 4.41(t, J=5.1 Hz, 2H), 3.97 (t, J=3.8 Hz, 1H), 3.91 (t, J=6.0 Hz, 1H), 3.86(m, 1H), 3.69 (m, 1H), 3.40 (dt, J=5.1, 6.5 Hz, 4H), 3.14 (dt, J=5.8,6.5 Hz, 4H), 1.55 (quint, J=6.5 Hz, 2H), 1.54 (quint, J=6.5 Hz, 2H). ¹³CNMR (DMSO-d₆) δ 173.14, 172.28, 73.28, 72.94, 71.66, 70.38, 58.59 (2C),35.78, 35.70, 32.17, 32.13.

Example 15 N¹,N⁶-Bis[2-(4-hydroxyphenyl)ethyl]-D-glucaramide

To a solution of tyramine (0.54 g, 3.93 mmol) in methanol (10 mL) in a20-mL scintillation vial equipped with a magnetic stirbar was added asolution of GDL (0.33 g, 1.88 mmol) in methanol (2 mL). The resultingsolution was stirred at ambient temperature for 15 hours. The resultingwhite precipitate was collected by filtration, washed with methanol (15mL), and dried under vacuum to give 0.62 g (74% yield). ¹H (300 MHz,DMSO-d₆) δ 9.10 (br, 2H), 7.84 (br t, 1H), 7.58 (br t, 1H), 6.98 (d,J=7.8 Hz, 4H), 6.67 (d, J=7.8 Hz, 4H), 5.47 (br, 2H), 4.70 (br, 2H),3.99 (s, 1H), 3.92 (m, 2H), 3.73 (br s,1H), 3.24 (br s, 4H), 2.60 (br t,4H). ¹³C NMR (75 MHz, DMSO-d₆) δ 173.28, 172.34, 155.83 (2C), 129.65(6C), 115.37 (4C), 73.46, 73.11, 71.85, 70.61, 40.56, 40.46, 34.62,34.54.

Bis(alkoxycarbonylalkyl)aldaramides Example 16N¹,N⁶-Bis(methoxycarbonylmethyl)-D-glucaramide

In a dry box, glycine methyl ester hydrochloride (0.13 g, 1.05 mmol) wasweighed into an oven-dried, 20-mL scintillation vial equipped with amagnetic stirbar. Methanol (4 mL) was added, and the solution wastreated with triethylamine (0.22 mL, 1.58 mmol). After the resultingsolution had stirred at ambient temperature for 10 minutes, a solutionof GDL (0.92 g, 0.53 mmol) in methanol (2 mL) was added, and theresulting solution was stirred overnight at ambient temperature. Theresulting white precipitate was collected by filtration, washed withmethanol (4 mL), and dried under vacuum to give 88 mg (48% yield). ¹HNMR (500 MHz, DMSO-d₆) δ 8.19 (t, J=5.8 Hz, 1H), 7.96 (t, J=5.8 Hz, 1H),5.69 (d, J=5.8 Hz, 1H), 5.40 (d, J=4.5 Hz, 1H), 4.65 (d, J=4.2 Hz, 1H),4.48 (d, J=6.0 Hz, 1H), 4.06 (br t, 1H), 4.01 (t, J=5.8 Hz, 1H),3.95-3.76 (m, 6H), 3.622 (s, 3H), 3.618 (s, 3H). ¹³C NMR (126 MHz,DMSO-d₆) δ 173.82, 172.97, 170.46, 170.35, 73.25, 72.80, 71.930, 70.64,51.90, 51.86, 40.68, 40.66.

Example 17 N¹,N⁶-Bis[(1S)-1-(methoxycarbonyl)ethyl]-D-glucaramide

In a dry box, L-alanine methyl ester hydrochloride (1.145 g, 8.20 mmol)was dissolved in 10 mL of methanol in an oven-dried, 50-mL round-bottomflask equipped with a magnetic stirbar. Addition of solid sodiumhydroxide (0.328 g, 8.20 mmol) and stirring at ambient temperature forthirty minutes resulted in a colorless slurry. A solution of GDL (0.714g, 4.10 mmol) in methanol (10 mL) was added, and the mixture was stirredfor two weeks at ambient temperature, forming a yellow-orange solutionwith precipitate. Evaporation of solvent under vacuum gave the productadmixed with sodium chloride. ¹H NMR (300 MHz, DMSO-d₆) δ 8.13 (d, J=7.3Hz, 1H), 7.95 (d, J=7.2 Hz, 1H), 5.20 (br, 4H), 4.32 (quint, J=7 Hz,1H), 4.30 (quint, J=7 Hz, 1H), 4.04 (d, J=3.5 Hz, 1H), 3.99 (d, J=5.6Hz, 1H), 3.87 (t, J=2.9 Hz, 1H), 3.71 (dd, J=2.8, 5.3 Hz, 1H), 3.61 (s,6H), 1.28 (d, J=7.2 Hz, 6H). ¹³C NMR (75 MHz, DMSO-d₆) δ 173.24, 173.02(2C), 172.42, 73.26, 72.76, 71.71, 70.50, 52.16 (2C), 47.58, 47.52,17.56, 17.35.

Example 18N¹,N⁶-Bis[(5S)-5-amino-5-(methoxycarbonyl)pentyl]-D-glucaramide

To a suspension of L-lysine methyl ester dihydrochloride (1.00 g, 4.29mmol) in 10 mL of methanol was added 1.22 mL (8.16 mmol) of1,8-diazabicyclo[5.4.0]undec-7-ene. A solution of GDL (373 mg, 2.14mmol) in 2 mL of methanol was added dropwise to the resultinghomogeneous solution. After the reaction had stirred at room temperaturefor 1 day, evaporation of solvent under vacuum and examination by ¹H NMRshowed the product to contain a 45:1 ratio of lysine acylated on theε-amine versus the α-amine group. ¹H NMR (500 MHz, DMSO-d₆) δ 7.82 (t,J=5.7 Hz, 1H), 7.59 (t, J=5.8 Hz, 1H), 3.97 (d, J=3.7 Hz, 1H), 3.91 (d,J=6.4 Hz, 1H), 3.85 (t, J=3.4 Hz, 1H), 3.66 (dd, J=2.9, 6.3 Hz, 1H),3.59 (s, 6H), 3.27 (m, 2H), 3.04 (m, 4H), 1.53-1.26 (m, 12H). ¹³C NMR(126 MHz, DMSO-d₆) δ 176.27 (2C), 173.30, 172.33, 73.53, 73.19, 71.73,70.57, 53.98 (2C), 51.56 (2C), 38.33, 38.25, 34.34 (2C), 29.05, 28.96,22.68, 22.66.

Example 19N¹,N⁶-Bis[(5S)-5-amino-5-(methoxycarbonyl)pentyl]-D-glucaramide(Alternate Procedure)

To a solution of L-lysine methyl ester dihydrochloride (0.341 g, 1.46mmol) in 5 mL of methanol was added a solution of sodium hydroxide(0.117 g, 2.93 mmol) in methanol (5 mL). After stirring at ambienttemperature for 25 minutes, the mixture was filtered to removeinsolubles, and a solution of GDL (0.127 g, 7.31 mmol) in methanol (5mL) was added. The reaction stirred several days at ambient temperature,and solvent was removed under vacuum to give 0.296 g (75% yield). ¹H NMRshowed the product to contain a 17:1 ratio of lysine acylated on theε-amine versus lysine acylated on the α-amine group.

Bis(carboxyalkyl)aldaramides Example 20N¹,N⁶-Bis[(1S)-1-carboxyethyl]-D-glucaramide

In a dry box, solid sodium hydroxide (0.449 g, 11.2 mmol) was added to aslurry of L-alanine (1.00 g, 11.2 mmol) in methanol (10 mL) in anoven-dried, 50-mL round-bottom flask equipped with a magnetic stirbar.The mixture stirred at room temperature for three hours, resulting in acolorless solution. GDL (0.977 g, 5.61 mmol) in methanol (8 mL) wasadded, and the mixture was stirred for 18 hours at ambient temperature.Methanol (6 mL) was added to the clay-like reaction mixture tofacilitate stirring for an additional 24 hours. Attempted recovery ofthe product by filtration failed due to clogging of the fritted glassfunnel. Evaporation of the solvent under vacuum gave the product as itsdisodium salt (1.091 g, 49% yield): ¹H NMR (300 MHz, D₂O) δ 4.31 (br s,1H), 4.26 (d, J=5.4 Hz, 1H), 4.19 (q, J=7.1 Hz, 2H), 4.11 (br s, 1H),3.95 (t, J=4.7 Hz, 1H), 1.37 (d, J=7.1 Hz, 6H). ¹³C NMR (75 MHz, D₂O) δ180.14, 179.98, 173.59 (2C), 73.63, 73.33, 72.60, 71.07, 51.20, 51.14,18.50, 18.24. Treatment of the disodium salt with stoichiometric HClgave the dicarboxylic acid: ¹H NMR (300 MHz, DMSO-d₆) δ 7.90 (d, J=6.9Hz, 1H), 7.73 (d, J=6.8 Hz, 1H), 4.23 (q, J=6.6 Hz, 2H), 4.03 (br s,1H), 3.98 (d, J=5.3 Hz, 1H), 3.89 (br s, 1H), 3.72 (br s, 1H), 1.28 (d,J=6.7 Hz, 6H). ¹³C NMR (75 MHz, DMSO-d₆) δ 174.25, 174.21, 172.94,172.11, 73.48, 72.77, 71.74, 70.49, 47.71, 47.65, 18.14, 17.85.

Example 21 N¹,N⁶-Bis[(1S)-1-carboxybutyl]-D-glucaramide

Solid sodium hydroxide (0.125 g, 3.13 mmol) was added to a slurry ofL-norvaline (0.366 g, 3.13 mmol) in methanol (11 mL) in an oven-dried,50-mL round-bottom flask equipped with a magnetic stirbar. The mixturestirred at room temperature for 30 minutes, resulting in a colorlesssolution. GDL (0.272 g, 1.56 mmol) in methanol (6 mL) was added, and themixture was stirred for 85 hours at ambient temperature. The resultingprecipitate was collected by filtration, washed with methanol (8 mL),and dried under vacuum to give 0.186 g (25% yield). ¹H NMR (D₂O) δ 4.31(d, J=3.4 Hz, 1H), 4.29 (d, J=5.5 Hz, 1H), 4.22 (t, J=4.8 Hz, 2H), 4.21(t, J=4.5 Hz, 4H), 4.12 (dd, J=3.6, 4.1 Hz, 1H), 3.97 (dd, J=4.4, 5.1Hz, 1H), 1.77 (m, 4H), 1.32 (m, 4H), 0.89 (t, J=7.5 Hz, 6H). ¹³C NMR(D₂O) δ 179.7, 179.6, 173.8, 173.6, 73.3, 73.2, 72.7, 71.0, 55.3, 55.2,34.4, 34.2, 19.0, 18.9, 13.5 (2C).

Example 22 N¹,N⁶-Bis[(5S)-5-amino-5-carboxypentyl]-D-glucaramide

Saponification ofN¹,N⁶-bis[(5S)-5-amino-5-(methoxycarbonyl)pentyl]-D-glucaramide gaveN¹,N⁶-bis[(5S)-5-amino-5-carboxypentyl]-D-glucaramide as its doubleinternal salt. ¹H NMR (D₂O) δ 4.30 (d, J=3.2 Hz, 1H), 4.23 (d, J=5.6 Hz,1H), 4.08 (dd, J=3.6, 4.6 Hz. 1H), 3.94 (dd, J=4.7, 5.6 Hz, 1H), 3.73(t, J=6.0 Hz, 2H), 3.27 (t, J=7.2 Hz, 4H), 1.88 (m, 4H), 1.59 (m, 4H),1.40 (m, 4H). ¹³C NMR (D₂O) δ 175.2 (2C), 174.5, 174.3, 73.4, 73.3,72.8, 71.2, 55.2 (2C), 39.1 (2C), 30.5. (2C), 28.5 (2C), 22.2 (2C).

Example 23N¹,N⁶-Bis[(5S)-5-(tert-butoxycarbonylamino)-5-carboxypentyl]-D-glucaramide

To a solution of N^(α)-tert-butoxycarbonyl-L-lysine (2.094 g, 8.50 mmol)in 15 mL of methanol was added a solution of sodium hydroxide (340 mg,8.50 mmol) in 15 mL of methanol, followed by a solution of GDL (740 mg,4.25 mmol) in 15 mL of methanol. After the reaction had stirred at roomtemperature for 1 day, the solvent was evaporated under vacuum to givethe product as its disodium salt. ¹H NMR (300 MHz, methanol-d₄) δ 4.21(d, J=2.9Hz, 1H), 4.14 (d, J=6.4Hz, 1H), 4.10 (t, J=2.8Hz, 1H), 3.93 (m,2H), 3.89 (dd, J=2.6, 6.4 Hz, 1H), 3.24 (t, J=6.5 Hz, 4H), 1.82-1.384(m, 12H), 1.43 (s, 18H). ¹³C NMR (75 MHz, methanol-d₄) δ 179.80 (2C),175.44, 174.94, 157.60 (2C), 79.96 (2C), 75.06, 75.00, 73.37, 71.72,57.14 (2C), 39.83 (2C), 33.80 (2C), 30.08 (2C), 28.81 (6C), 23.78 (2C).

1. A compound of Formula I

and salts thereof, wherein n=4 and R¹ and R² are independently selectedfrom optionally substituted hydrocarbylene groups, wherein thehydrocarbylene groups are aliphatic or aromatic, linear, branched, orcyclic, and wherein the hydrocarbylene groups optionally contain —O—linkages.
 2. The compound of claim 1 wherein R¹ and R² are independentlyselected from alkylene, polyoxaalkylene, and arylene groups, linear orbranched, and wherein the alkylene, polyoxaalkylene, or arylene groupsare optionally substituted with NH₂ or alkyl.
 3. The compound of claim 1wherein R¹ and R² are the same.
 4. The compound of claim 1 wherein R¹and R² are independently selected from: —CH₂-CH₂—, —CH₂(CH₂)₄CH₂—, andcompounds of Formula II, Formula III, and Formula IV,

wherein the open valences indicate where R¹ and R² are attached to thenitrogens in Formula I and wherein, when R¹ or R² is Formula IV, eitheropen valence can be attached to the terminal, primary amino (NH₂) groupof Formula I.
 5. A compound of Formula I

and salts thereof, wherein n=2 and wherein R¹ and R² are compounds ofFormula IV,

wherein the open valences indicate where R¹ and R² are attached to thenitrogens in Formula I and wherein either open valence can be attachedto the terminal, primary amino (NH₂) group of Formula I.